Amine salts of pitavastatin and rosuvastatin

ABSTRACT

The present invention relates to unsaturated amine salts of HMG-CoA reductase inhibitors, to a method of producing said amine salts and to the use of said amine salts in the production of pharmaceutically acceptable salts of HMG-CoA reductase inhibitors.

FIELD OF THE INVENTION

The present invention relates to unsaturated amine salts of HMG-CoAreductase inhibitors, to a method of producing said amine salts and tothe use of said amine salts in the production of pharmaceuticallyacceptable salts of HMG-CoA reductase inhibitors.

BACKGROUND OF THE INVENTION

HMG-CoA reductase inhibitors, also known as statins, are widely useddrugs prescribed to treat hypercholesterolemia, hyperlipoproteinemia,and atherosclerosis. Examples of HMG-CoA reductase inhibitors areatorvastatin, fluvastatin, lovastatin, mevastatin, pitavastatin,pravastatin, rosuvastatin and simvastatin.

Production of HMG-CoA reductase inhibitors is known and includes(bio)-chemical conversion, chromatography, crystallization extraction,fermentation and the like. Some HMG-CoA reductase inhibitors, likelovastatin, are produced by fermentation using microorganisms ofdifferent species identified as species belonging to Aspergillus,Monascus, Nocardia, Amycolatopsis, Mucor or Penicillium genus. Some,like mevastatin, pravastatin and simvastatin, are obtained by treatingthe fermentation products using the methods of chemical or enzymaticsynthesis. Others, like atorvastatin, fluvastatin, pitavastatin androsuvastatin, are the products of total chemical synthesis.

In several cases, production of HMG-CoA reductase inhibitors includesisolation and purification through salt formation. For example, in U.S.Pat. No. 4,319,039 and U.S. Pat. No. 4,342,767, the ammonium salt oflovastatin is isolated from the organic phase which has been extractedfrom the fermentation medium. In the same documents the ethylenediamine, tetramethyl ammonium, potassium and N-methylglucamine salts aswell as salts of different amino acids such as L-arginine, L-lysine andL-ornithine is described. EP 65,835 discloses the preparation of thetert-octyl amine and L-ornithine salts of certain modified HMG-CoAreductase inhibitors, whereby also other salts with amines such asammonia, amino acids or organic amines like benzyl amine, cycloheptylamine, cyclohexyl amine, cyclopentyl amine, dibenzyl amine, dicyclohexylamine, N,N-diethylbenzyl amine, N,N-diethylcycloheptyl amine,N,N-dimethylbenzyl amine, N,N-dimethylcyclohexyl amine,N,N-dimethylcyclopentyl amine, N-ethylcycloheptyl amine,N-ethylcyclohexyl amine, 2-ethylhexyl amine, N-ethyl-N-methylbenzylamine, N-methylbenzyl amine, 2-methylbenzyl amine, N-methylcyclopentylamine, N-methylpiperidine, N-methylpyrrolidine, morpholine, octyl amine,phenethyl amine, piperidine, pyrrolidine and tribenzyl amine arementioned. U.S. Pat. No. 5,763,646 and U.S. Pat. No. 5,763,653 disclosethe preparation of the cyclopropyl amine and n-butyl amine salts oflovastatin and their use in a process of chemical semi synthesis ofsimvastatin. U.S. Pat. No. 5,403,860 discloses amine salts ofoctahydronaphthalene oxime derivatives of HMG-CoA reductase inhibitorsML-236A, ML-236B, MB-530A and MB-530B. As final amine salts, dibenzylamine, dicyclohexyl amine, D-glucosamine, morpholine, tert-octyl amineand D-phenylglycine alkyl ester salts are mentioned. WO 00/17150describes amine salts of HMG-CoA reductase inhibitors in the process forsemi synthetic preparation of HMG-CoA reductase inhibitors and theconversion of the amine salts of HMG-CoA reductase inhibitors into thepharmaceutically acceptable salts of the HMG-CoA reductase inhibitors.WO 00/17150 mentions atorvastatin, fluvastatin, lovastatin, mevastatin,pravastatin and simvastatin as HMG-CoA reductase inhibitors on the onehand and a wide range of alkyl amines on the other hand, preferredexamples of which are straight, branched or cyclic alkyl amines such astert-amyl amine, n-butyl amine, sec-butyl amine, tert-butyl amine,cyclohexyl amine, dibutyl amine, dicyclohexyl amine,N,N′-diisopropylethylene diamine and N-methyl-cyclohexyl amine.

The first reports of amine salts of rosuvastatin are of a more recentdate. For example, WO 2010/081861 describes the preparation of aminesalts of rosuvastatin and their use in the preparation of the calciumsalt of rosuvastatin. Amines disclosed by WO 2010/081861 includesec-butyl amine, tert-butyl amine, cycloheptyl amine and cyclopentylamine. Other amine salts of rosuvastatin are disclosed in WO 2012/073256(rosuvastatin salts of lysine, arginine, triethanol amine, ethanolamine, choline, epolamine, meglumine and ethylene diamine), WO2012/063115 (rosuvastatin salts of thioureas, heterocyclic amines suchas tetrahydrofurfuryl amine, azoles, amino acids, triazoles andpyridines); WO 2012/046193 (rosuvastatin salts of histidine and lysine);WO 2010/035284 (rosuvastatin salts of (S)-2-amino-3,3-dimethyl butaneand (S)-(−)-α-methylbenzyl amine), WO 2001/60804 (rosuvastatin salts ofammonium, methyl ammonium, ethyl ammonium, diethanol ammonium,tri(hydroxymethyl)-methyl ammonium, benzyl ammonium, and 4-methoxybenzylammonium) and WO 2005/077916 (rosuvastatin salts of cyclohexyl ammonium,diisopropyl ammonium, isopropyl ammonium, dicyclohexyl ammonium, and(S)-(+)-a-methylbenzyl ammonium).

For pitavastatin, the number of disclosures of amine salts is morelimited. In EP 742209 short chain (1-3) alkyl amine salts ofpitavastatin are disclosed, in WO 2007/132482 the arginine salt isdisclosed while WO 2012/106584 discloses diethanol amine and megluminesalts of pitavastatin.

Driven by the pressure to avail medication such as HMG-CoA reductaseinhibitors at affordable prices, industry is in constant need forprocess rationalization and optimization. There is thus a need forstarting substances and intermediates that are of high purity that canbe prepared using simple and low cost techniques. From this perspective,it is an aim of the invention to provide alternative amine salts ofHMG-CoA reductase inhibitors that can be used in the production ofHMG-CoA reductase inhibitors.

DETAILED DESCRIPTION OF THE INVENTION

In a first aspect the invention provides an amine salt of HMG-CoAreductase inhibitors wherein said amine is unsaturated. It wassurprisingly found that HMG-CoA reductase inhibitors readily form saltswith unsaturated amines and crystallize once they are formed. It hasbeen found that crystals of the unsaturated amine salt of the desiredHMG-CoA reductase inhibitor of high purity may be obtained fromsolutions comprising a large number of impurities and undesired HMG-CoAreductase inhibitor analogs.

In a first embodiment the amine is unsaturated. In this respect, theterm unsaturated refers to at least one double bond or at least onetriple bond between two carbon atoms. The unsaturated amine may bestraight, branched or cyclic. Preferred examples are allyl amine,3-amino-3-methyl-1-propyne), cumyl amine, 2-furfuryl amine, 3-furfurylamine and propargyl amine (3-amino-1-propyne).

In a second embodiment the unsaturated amine comprises an oxygen atomand preferably said oxygen atom is in the form of an ether bond. Theunsaturated amine comprising an oxygen atom may be straight, branched orcyclic. Preferred examples are 2-furfuryl amine and 3-furfuryl amine.Furfurylamine is present as a key structural element in Furosemide (adiuretic used for hypertension and edema), and it is used in skin carecosmetics for anti-aging.

Furfural and derivatives have favorable toxicological properties, seefor example “Furfural and Derivatives”, H. E. Hoydonkx et al., pp.285-313, in: Ullmann's Encyclopedia of Industrial Chemistry, 2012,Wiley-VHC Verlag, Weinheim, Germany.

In a third embodiment the HMG-CoA reductase inhibitor preferably isatorvastatin, fluvastatin, pitavastatin or rosuvastatin. It has beenfound that formation of the amine salt of a HMG-CoA reductase inhibitorcan be combined in a single process step with the deprotection sequencethat is usually required in the synthesis of HMG-CoA reductaseinhibitors that are made through total synthesis. During productioncarboxyl and hydroxyl functions of these molecules need to be protectedand protective groups are removed at the final stage of the synthesis.Removal of protective groups usually includes an acidic treatment. Itwas found that the amines of the present invention not only are suitablefor formation of stable and pure salts but simultaneously can functionto neutralize acidic conditions, thereby preventing the formation ofadditional foreign salts.

In a second aspect, the present invention provides a process for thepreparation of salts of HMG-CoA reductase inhibitors with amines asspecified in the first aspect of the invention.

In one embodiment, the process may be performed as follows. A protectedderivative of the HMG-CoA reductase inhibitor, for example the methylester of pitavastatin acetonide or rosuvastatin acetonide, is dissolvedor suspended in a suitable solvent, for example acetonitrile. Removal ofprotecting groups may be carried out by treatment with acid followed bytreatment with base, or vice versa. Optionally the organic solvent maybe changed by distillation followed by addition of a second solvent, forexample ethyl acetate. Preferably the aqueous phase is removed afterwhich the amine of choice is added to the organic phase. Preferably theamount of amine added is from 1.0 to 2.0 mole-equivalents compared tothe HMG-CoA reductase inhibitor. The resulting mixture can optionally beconcentrated in order to reduce mother liquor losses, if any. Thedesired amine salt of the HMG-CoA reductase inhibitor precipitates orcrystallizes and can be isolated following simple techniques known tothe skilled artisan, such as centrifugation, decantation, filtration andthe like. Preferably the salt thus obtained is washed with the samesolvent as used for the crystallization/precipitation process.Optionally the amine salt of the HMG-CoA reductase inhibitor may bere-crystallized, for instance from an alternate solvent such asacetonitrile.

It was found that furfurylamine, having a boiling point of 145° C., canbe advantageously removed via distillation instead of extraction. Ingeneral, not many high-boiling amines can be removed in this way, asthey require more lengthy and less economical extraction procedures.

In a third aspect, the present invention provides a process for thepreparation of metal salts of HMG-CoA reductase inhibitors. Preferablysaid metal salts are pharmaceutically acceptable, examples of which arecalcium and magnesium. Contrary to the teaching of U.S. Pat. No.5,403,860 that lower yields are obtained when using the salts of HMG-CoAreductase inhibitors as starting or intermediate substances, we havefound that, when using the amine salts of HMG-CoA reductase inhibitorsaccording to the present invention, the yields and the purity of theprepared HMG-CoA reductase inhibitors are equal to or greater than whenusing the HMG-CoA reductase inhibitors in the lactone form. Thus, it wasfound that in processes for the synthetic construction of HMG-CoAreductase inhibitors the formation of amine salts of HMG-CoA reductaseinhibitors in the synthetic medium, in comparison with the mere metalsalts as described in publicly accessible literature, represents anefficient means for the isolation and/or purification of HMG-CoAreductase inhibitors by simple crystallization. The amines which aredescribed in the present invention and which readily form salts withHMG-CoA reductase inhibitors are thus particularly suitable as auxiliarymaterials or processing aids for the isolation and/or purification ofHMG-CoA reductase inhibitors. Accordingly, the novel amine salts ofHMG-CoA reductase inhibitors of the present invention are also highlyvaluable as such.

EXAMPLES Example 1 Preparation of Amine Salts of pitavastatin androsuvastatin

The methyl ester of pitavastatin acetonide (1a, R₂=R₃=R₄=CH₃; 5.6 mmol)or rosuvastatin acetonide (1b, R₂=R₃=R₄=CH₃; 5.6 mmol) was added toacetonitrile (21 mL). The mixture was heated to 35° C. until completedissolution was obtained. To the solution 0.02 N aqueous HCl (9 mL) wasadded over a period of 1 h. The mixture was stirred for 12 h, followedby addition of 1 N aqueous NaOH in 15 min until pH=12. After stirringfor 1 h, the mixture was concentrated under vacuum to removeacetonitrile. Next, ethyl acetate (30 mL) was added followed by additionof 1 N aqueous HCl until pH=4. The ethyl acetate phase was separated. Tothe ethyl acetate phase was added over a period of 30 min, 1 equiv. (5.6mmol) of amine (see Table below) dissolved in ethyl acetate (10 mL).Upon addition, a white precipitate was formed. The resulting slurry wasstirred for 1h, followed by filtration of the amine salt of the HMG-CoAreductase inhibitor pitavastatin or rosuvastatin. The amine salt waswashed with ethyl acetate (2×5 mL), dried and re-crystallized fromacetonitrile.

HMG-CoA Product Formula Reductase Inhibitor Amine R₄ Pitavastatin2-Furfuryl amine 2a

Pitavastatin Propargyl amine 2a

Rosuvastatin 2-Furfuryl amine 2b

Rosuvastatin Propargyl amine 2b

Example 2 Preparation of the Calcium Salts of pitavastatin androsuvastatin

The amine salt of the HMG-CoA reductase inhibitor pitavastatin orrosuvastatin obtained in Example 1 was added to water (20 mL) and the pHwas adjusted to 12 with 1 N aqueous NaOH. The reaction mixture wasextracted with ethyl acetate (20 mL). The organic phase was separatedand the aqueous phase was concentrated to 15 mL. To the obtained clearaqueous solution was added in portions over a period of 1 h, 7 mL of asolution of 4.5 w/w % Ca(OAc)₂.H₂O in water. Upon addition whiteprecipitate was formed. After 1 h the precipitate was filtered and driedto give the calcium salt of pitavastatin or rosuvastatin as a whitesolid.

Example 3 Preparation of rosuvastatin-Ca ((2b), R₄=Ca²⁺) from((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetatemethyl ester ((1b), R₂=R₃=R₄=CH₃)

2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetatemethyl ester (3.0 g, 5.6 mmol) was added to acetonitrile (21 mL). Themixture was heated to 35° C. until complete dissolution was obtained. Tothe solution, 0.02 N aqueous HCl (9 mL) was added over a period of 1 h.The mixture was stirred for 12 h, followed by addition of 1 N aqueousNaOH in 15 min until pH=12. After stirring for 1 h, the mixture wasconcentrated under vacuum to remove the acetonitrile. Next ethyl acetate(30 mL) was added followed by addition of 1 N aqueous HCl until pH=4.The ethyl acetate phase was separated. To the ethyl acetate phase wasadded over a period of 30 min, 1 equiv. of the amine dissolved in ethylacetate (10 mL). Upon addition, a white precipitate was formed. Theresulting slurry was stirred for 1 h, followed by filtration of therosuvastatin-amine salt. The salt was washed with ethyl acetate (2×5 mL)and dried. The salt was re-crystallized from acetonitrile.

The salt was added to water (20 mL) and the pH was adjusted to 12 with 1N aqueous NaOH. The reaction mixture was extracted with ethyl acetate(20 mL) and the organic phase was separated. The aqueous phase wasconcentrated to 15 mL. To the obtained clear aqueous solution was addedin portions over a period of 1 h, 7 mL of a solution of 4.5 w/w %Ca(OAc)₂.H₂O in water. Upon addition white precipitate was formed. After1 h the precipitate was filtered and dried to give 2.1 g of the calciumsalt of rosuvastatin as a white solid (yield 72%). ¹H NMR (300 MHz,DMSO): δ7.72 (dd, 2H), 7.29 (t, 2H), 6.51 (d, 1H), 5.54 (dd, 1H), 4.21(dd, 1H), 3.71 (m, 1H), 3.55 (s, 3H), 3.51-3.41 (m, 4H), 2.09 (dd, 1H),1.92 (dd, 1H), 1.57-1.42 (m, 1H), 1.36-1.25 (m, 1H), 1.22 (dd, 6H).

Example 4 Preparation of rosuvastatin-Ca ((2b), R₄=Ca²⁺) from2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetatemethyl ester ((1b), R₂=R₃=R₄=CH₃) via furfuryl amine salt

2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetatemethyl ester (3.0 g, 5.6 mmol) was added to acetonitrile (21 mL). Themixture was heated to 35° C. until complete dissolution was obtained. Tothe solution, 0.02 N aqueous HCl (9 mL) was added over a period of 1 h.The mixture was stirred for 12 h, followed by addition of 1 N aqueousNaOH in 15 min until pH=12. After stirring for 1 h, the mixture wasconcentrated under vacuum to remove the acetonitrile. Next ethyl acetate(30 mL) was added followed by addition of 1 N aqueous HCl until pH=4.The ethyl acetate phase was separated. The ethyl acetate phase washeated to 50° C. Then furfurylamine (0.82 g, 8.4 mmol, 1.5 equiv.)dissolved in ethyl acetate (10 mL) was added in 10 min. Upon addition, awhite precipitate was formed. The reaction mixture was cooled to 20-25°C. and stirred for 2 h, followed by filtration of the rosuvastatinfurfuryl amine salt. The salt was washed with ethyl acetate (2×5 mL) anddried. The salt was added to acetonitrile (20 mL) and heated to 60° C.until complete dissolution. The solution was cooled to 20-25° C. and theresulting slurry was stirred for 2 h. The rosuvastatin furfuryl aminesalt was isolated by filtration, washed with acetonitrile (2×5 mL) anddried.

The salt was added to water (20 mL) and the pH adjusted to 3 with 1Naqueous HCl. The reaction mixture was extracted with MTBE (20 mL). Theorganic phase was separated and extracted with 1N aqueous NaOH. Theaqueous phase was separated and concentrated to 15 mL. To the obtainedclear aqueous solution was added in portions over a period of 1 h, 7 mLof a solution of 4.5 w/w % Ca(OAc)₂.H₂O in water. Upon addition whiteprecipitate was formed. After 1 h the precipitate was filtered and driedto give the calcium salt of rosuvastatin as a white solid (2.1 g, yield72%). From the filtrate, the Rosuvastatin can be recovered in order toincrease the overall yield. For example, this can be done, afteracidification to pH=4 and extraction with methyl tert butylether byformation of the amine salt as described in this example. In anotherembodiment, this filtrate can be combined with the extraction procedureas described in the example leading to a single step.

Example 5 Preparation of rosuvastatin-Ca ((2b), R₄=Ca²⁺) from2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetatemethyl ester ((1b), R₂=R₃=R₄=CH₃) via propargyl amine salt

2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetatemethyl ester (3.0 g, 5.6 mmol) was added to acetonitrile (21 mL). Themixture was heated to 35° C. until complete dissolution was obtained. Tothe solution, 0.02 N aqueous HCl (9 mL) was added over a period of 1 h.The mixture was stirred for 12 h, followed by addition of 1 N aqueousNaOH in 15 min until pH=12. After stirring for 1 h, the mixture wasconcentrated under vacuum to remove the acetonitrile. Next ethyl acetate(30 mL) was added followed by addition of 1 N aqueous HCl until pH=4.The ethyl acetate phase was separated. The ethyl acetate phase washeated to 50° C. Then propargyl amine (0.46 g, 8.4 mmol, 1.5 equiv.)dissolved in ethyl acetate (10 mL) was added in 10 min. Upon addition, awhite precipitate was formed. The reaction mixture was cooled to 20° C.and stirred for 3 h, followed by filtration of the salt. The salt waswashed with ethyl acetate (2×5 mL) and dried. The salt was added toacetonitrile (20 mL of) and heated to 40° C. until complete dissolution.The solution was cooled to 20° C. and the resulting slurry was stirredfor 2 h. The rosuvastatin propargyl amine salt was isolated byfiltration, washed with acetonitrile (2×5 mL) and dried.

The salt was added to water (25 mL) and the pH adjusted to 12 with 1Naqueous NaOH. The solution was concentrated to 15 mL, followed byaddition of 7 mL of a solution of 4.5 w/w % Ca(OAc)₂.H₂O in water in 1hour. Upon addition white precipitate was formed. After 2 h theprecipitate was filtered and dried to give the calcium salt ofrosuvastatin as a white solid (2.2 g, yield 74%).

Example 6 Preparation of2-((4R,6S)-6-((E)-2-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)vinyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate,methyl ester from2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-carbaldehyde and2-((4R,6S)-6-((benzo[d]thiazol-2-ylsulfonyl)methyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetatemethyl ester

2-((4R,6S)-6-((Benzo[d]thiazol-2-ylsulfonyl)methyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetatemethyl ester (35.0 g, 87 mmol) and2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-carbaldehyde (23.9 g, 82mmol) were added to 78 mL of N-methyl-2-pyrrolidone and 280 mL of2-methyltetrahydrofuran. The mixture was heated until 50° C. andfiltered. The solution was cooled to −62° C., followed by addition of 54mL of 2M NaO—tBu in tetrahydrofuran (108 mmol) in 2.5 h keeping thetemperature between −55 and −60° C. The temperature was allowed toincrease to −20° C. and quenched with 200 mL of water. The mixture wastransferred to another reactor using 30 mL of 2-methyltetrahydrofuranand the reaction mixture heated to 50° C. The pH was adjusted to 12 with29 mL of 4N aqueous NaOH. The layers were separated. The organic phasewas washed 2 times with 200 mL of a 5 w/w % aqueous NaCl solution,whereby the pH was adjusted to 12 using 4N aqueous NaOH, followed by 1time with 100 mL of a 5 w/w % aqueous NaCl solution, whereby the pH wasadjusted to 12 with 4N aqueous NaOH. Finally, the organic phase waswashed with 100 mL of 5 w/w % aqueous NaHCO₃. The organic layer wasevaporated to give a thick oil. The solid was re-crystallized from 200mL of isopropanol to give2-((4R,6S)-6-((E)-2-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)vinyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate,methyl ester as a white solid (32.1 g, yield 77.6%) with an HPLC purityof 99.7%.

The ¹H NMR data of this compound were in agreement with the literaturedata, see Hiyama T.; Minami T.; Yanagawa Y.; Ohara Y. WO 95/11898, 1995to Nissan Chemical Industries, example 4 of this patent).

Example 7 Preparation of2-((4R,6S)-6-((E)-2-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)vinyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate,methyl ester from2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-carbaldehyde and2-((4R,6S)-6-((benzo[d]thiazol-2-ylsulfonyl)methyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetatemethyl ester

2-((4R,6S)-6-((Benzo[d]thiazol-2-ylsulfonyl)methyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetatemethyl ester (30.0 g, 75 mmol) and2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-carbaldehyde (20.3 g, 70mmol) were added to 35 mL of N-methyl-2-pyrrolidone and 200 mL of2-methyltetrahydrofuran at 22° C. The reaction mixture was cooled to−60° C. Then 42 mL of 2M NaO—tBu in tetrahydrofuran (84 mmol) was addedin 2.5 h keeping the temperature between −55 and −60° C. The temperaturewas allowed to increase to −50° C. and quenched with 100 mL of water.The mixture was transferred to another reactor using 30 mL of2-methyltetrahydrofuran, heated to 50° C. and the pH adjusted to 12.6with 31 mL of 4N aqueous NaOH. The layers were separated. The organicphase was washed 2 times with 100 mL of a 5 w/w % aqueous NaCl solution,whereby the pH was adjusted each time to 12 using 4N aqueous NaOH. Next,the organic phase was washed with 100 mL of 5 w/w % aqueous NaHCO₃. Theorganic layer was evaporated to give a thick oil. The solid wasre-crystallized from 200 mL of isopropanol to give2-((4R,6S)-6-((E)-2-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)vinyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate,methyl ester as a white solid (29.0 g, yield 81.3%) with an HPLC purityof 99.5%.

Example 8 Preparation of Pitavastatin-Ca ((2a), R₄=Ca²⁺) from2-((4R,6S)-6-((E)-2-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)vinyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetatemethyl ester ((1a), R₂=R₃=R₄=CH₃)

2-((4R,6S)-6-((E)-2-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)vinyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetatemethyl ester (10.0 g, 21.0 mmol) was added to acetonitrile (50 mL). Themixture was heated to 45° C., followed by addition of 4N aqueous HCl(5.3 mL, 21 mmol). The reaction mixture was stirred for 1.5 h and cooledto 22° C. Then in total 12 mL of 4N aqueous NaOH was added until pH12.7. After stirring for 30 minutes, the pH was reduced to 9 by additionof acetic acid. The acetonitrile was removed via distillation undervacuum, followed by addition of 30 mL of water. To the clear solutionwas added over a period of 30 min, 47.3 mL of a solution of 4.5 w/w %Ca(OAc)₂.H₂O in water. Upon addition white precipitate was formed. After1 h the precipitate was filtered, washed with water (2×15 mL) and driedto give 9.0 g of the calcium salt of Pitavastatin as a solid. HPLCpurity 98.8%, KF 2.1% water.

Example 9 Preparation of Pitavastatin-Ca ((2a), R₄=Ca²⁺) from2-((4R,6S)-6-((E)-2-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)vinyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetatemethyl ester ((1a), R₂=R₃=R₄=CH₃) via furfuryl amine salt

2-((4R,6S)-6-((E)-2-(2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl)vinyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetatemethyl ester (10.0 g, 21.0 mmol) was added to acetonitrile (50 mL). Themixture was heated to 45° C. and 4N aqueous HCl (5 mL, 20 mmol) wasadded. The reaction was stirred for 2.5 h. After cooling to 22° C., 4Maqueous NaOH is added over a period of 1.5 h. The pH is reduced to 6.5by addition of 1N aqueous HCl, and then concentrated under vacuum toremove the acetonitrile. Next methyl tert-butylether (20 mL) was addedfollowed by addition of 1 N aqueous HCl until pH=4. The organic layerwas separated and concentrated under vacuum. To the residue was addedacetonitrile (68 mL) and water (3.9 mL). The reaction mixture was cooledto 10° C.; Then Then furfurylamine (2.04 g, 21.0 mmol) dissolved inacetonitrile (13.5 mL) was added in 1.5 h. Upon addition, a whiteprecipitate was formed. The reaction mixture was stirred for 30 min,followed by filtration of the Pitavastatin-furfuryl amine salt. The saltwas washed with ethyl acetate (2×10 mL) and dried to give 8.3 g of awhite solid.

The salt was added to water (100 mL) and the pH adjusted to 12.3 using3.4 mL aqueous 4N NaOH. The reaction mixture is heated and 3×40 mL ofwater was removed via distillation under vacuum. After eachdistillation, the volume distilled water was replaced by adding the samevolume of fresh water. After cooling to 22° C., 1 g of active carbon wasadded. The mixture was stirred for 1 h and the carbon removed byfiltration. The pH of the solution was lowered by addition of aceticacid to 9.7 and 20 mL of water was added. Then over a period of 45 min,33 mL of a solution of 4.5 w/w % Ca(OAc)₂.H₂O in water was added. Uponaddition white precipitate was formed. After 30 minutes stirring, thesolid was filtered and dried to give the calcium salt of

Pitavastatin as a white solid (7.5 g, KF 2.8%). From the filtrate, thePitavastatin can be recovered in order to increase the overall yield.For example, this can be done, after acidification to pH=4 andextraction with methyl tert butylether by formation of the amine salt asdescribed in this example. In another embodiment, this filtrate can becombined with the extraction procedure as described in the exampleleading to a single step.

Comparative Example Preparation of rosuvastatin-Ca ((2b), R₄=Ca²⁺) from2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetatemethyl ester ((1b), R₂=R₃=R₄=CH₃) via tert-butyl amine salt

2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetatemethyl ester (3.9 g, 7.2 mmol) was added to acetonitrile (23 mL). To themixture was added 0.02 N aqueous HCl (7.7 mL) and stirred for 18 h at20° C. Then 1N aqueous NaOH was added in 15 min until pH=12. Afterstirring for 1 h, the mixture was concentrated under vacuum to removethe acetonitrile. Next ethyl acetate (30 mL) was added followed byaddition of 1N aqueous HCl until pH=4. The ethyl acetate phase wasseparated. The ethyl acetate phase was heated to 60° C. and tert-butylamine (0.8 g, 11.0 mmol, 1.5 equiv.) dissolved in ethyl acetate (10 mL)was added. The reaction mixture was cooled to 40° C., when precipitationoccurred. The slurry was further cooled to 20° C. and stirred for 2 h atthis temperature. The solid was isolated by filtration and washed withethyl acetate (2×3 mL) and dried. The salt was added to acetonitrile (19mL) and water (1 mL) and heated to reflux. The reaction mixture wascooled to 20° C. and stirred for 1.5 h. The rosuvastatin tert-butylamine salt was isolated by filtration, washed with acetonitrile (2×5 mL)and dried.

The salt was added to water (30 mL) and the pH was adjusted to 12 with1N aqueous NaOH. The solution was concentrated to 20 mL. The pH wasadjusted to 8.5-9 with acetic acid. Then 8 mL of a solution of 4.5 w/w %Ca(OAc)₂.H_(w)O in water was added in 1 h. The reaction mixture wasstirred for 3 h and the solid isolated by filtration and washed withwater (2×5 mL). The solid was dried to give the calcium salt ofrosuvastatin as a white solid (2.9 g, yield 80%).

1. An amine salt of a HMG-CoA reductase inhibitor, wherein said amine comprises at least one unsaturated carbon-carbon bond.
 2. The amine salt of claim 1 wherein the amine comprises a compound selected from the group consisting of 2-furfuryl amine, 3-furfuryl amine and propargyl amine.
 3. The amine salt of claim 1, wherein the HMG-CoA reductase inhibitor is selected from the group consisting of pitavastatin and rosuvastatin.
 4. The amine salt of claim 3 which is the 2-furfuryl amine salt of rosuvastatin.
 5. A method for the preparation of the amine salt of claim 1 comprising the steps of: a) Contacting a protected derivative of a HMG-CoA reductase inhibitor with acid followed by base or with base followed by acid; b) Treating the mixture obtained in step a) with an amine; c) Isolating the amine salt obtained in step b), wherein said amine comprises at least one unsaturated carbon-carbon bond.
 6. Use of an amine salt of claim 1 in the preparation of amorphous or crystalline pitavastatin calcium salt or amorphous or crystalline rosuvastatin calcium salt. 